These studies demonstrate that Staphylococcus aureus Cowan I (SAC), a protein A-positive Staphylococcal strain, is a potent and consistent inducer of IgM rheumatoid factor production by normal human peripheral blood mononuclear cells. The frequency and magnitude of this response greatly exceeded that of parallel cultures stimulated with pokeweed mitogen or the protein A-negative S. aureus Wood strain, although all three agents induced a similar amount of total IgM. Cell fractionation studies indicated that SAC-induced IgM rheumatoid factor is T cell-dependent. The striking ability of SAC to induce IgM rheumatoid factor may relate to its protein A content, since cultures stimulated with protein A-coupled sepharose beads also consistently produced this autoantibody. Thus SAC is a new probe of in vitro IgM rheumatoid factor production and its use has provided further evidence that most healthy individuals harbor precursors of IgM rheumatoid factor secreting cells. Unlike other polyclonal activators, SAC is unique in its capacity to bind immunoglobulin, a property that may account for its prominent anti-IgG inducing capacity.